When crystallized, a given molecule may give rise to a variety of polymorphs and solvates each presenting distinct crystal structures and physical properties like solubility, melting points, desolvation temperatures, X-ray diffraction patterns, solid state NMR spectra, apparent and true densities, crystal friability, powder flowability, and/or powder compressibility.
As a result, a change in the crystalline form of a given drug may affect the safety and efficacy of the drug product (Knapman et al, K. Modern Drug Discoveries, March 2000:53). For example, many antibiotics, antibacterials, tranquilizers, etc., exhibit polymorphism and the polymorphic forms of a given drug may exhibit superior bioavailability and therefore have higher activity compared to other polymorphs. It is therefore crucial, upon the development of a novel therapeutic drug, to determine which polymorphic form or solvate is the most suited for the administration to a subject.
Phosphoantigens comprises a large group of phosphate-containing compounds that activate 76 T cells (Fournié et al, Res. Immunol., 1996, 147(5), 338-347, Belmant et al, FASEB, 2000, 14(12), 1669-1670, Espinosa et al, Microbes and Infections, 2001). CHDMAPP and related organo-phosphorous compounds, and their method of preparation and their therapeutic use, have been disclosed in U.S. Pat. No. 7,399,756. These organo-phosphorous compounds are useful in the activation of γδ T cells and are therefore promising agents for the treatment and prevention of cancer, infectious diseases and auto-immune diseases. One compound in particular, CHDMAPP, also named (2E)-1-hydroxy-2-methylpent-2-enyl-pyrophosphonate, (Boëdec A. et al, J Med. Chem. 2008 Mar. 27; 51(6):1747-54) has been proven to be a very potent activator of γδ T cells. Its in vitro activity is approximately 100 times higher than that of another known highly active γδ T cell compound BrHPP (Phosphostim™).
Traditional preparation of CHDMAPP is made in a convergent manner, in four steps according to publications from Hecht et al. (Hecht et al., Tetrahedron Letters, 43 (2002) 8929-8933) for the preparation of (E)-4-chloro-2-methylbut-2-en-1-ol, Miyashita et al. (Miyashita et al., J. Org. Chem. 42 (1977) 3772-3774) for the preparation of (E)-4-chloro-2-methylbut-2-en-1-(pyranyl-2′-oxy), this intermediate compound is coupled with a phosphonylating agent (obtained according to Valentijn et al., Synlett (1991) 663-664 and demethylated as reported by Phan and Poulter (J. Org. Chem. (2001), 66, 6705-6710)) to obtain the pyranyl-2′-oxy derivative.
Recent development have shown that phosphoantigens can form salts with selected organic bases, e.g. benzathine, to obtain a highly pure product in crystalline form, as disclosed in PCT publication no. WO 07/039,635. However, the solubility of theses salts in water is sometimes poor, which does not favour bioavailability (BCS class 2 or 4). Interestingly, only organic salts were found to be suitable for preparing pure crystalline phosphoantigens (such as the weak agonist IPP). BrHPP (commonly named Phosphostim™) does not appear to yield a stable crystalline form with a mineral base.
Because sodium is particularly well suited for pharmaceutical use, the organic salt of CHDMAPP is typically processed on an ion exchange resin to obtain CHDMAPP sodium salt as a solution in water. The obtained solution can be concentrated; ultimately, in certain cases the compound may be crystallized. This crystallisation step, conducted in standard conditions, leads to either a hygroscopic anhydrous solid compound or to a heterogeneous mixture of ill defined solid phases, the crystallisation of one form or the other being particularly hard to control. However, the obtained compound is not homogenous and may greatly vary upon two successive crystallisation steps. CHDMAPP can also be stored in liquid form. However; solid forms are in many cases preferable to liquid compositions for pharmaceutical purposes.
There remains therefore a need for novel phosphoantigen compound that is well characterized, in a homogenous solid form, presenting a very high stability, having improved processing properties, being water soluble and safe for direct administration to a patient.